Post-traumatic stress disorder (PTSD) is associated with cognitive deficits, oxidative
stress, and inflammation. Animal models have recapitulated features of PTSD, but no
comparative RNA sequencing analysis of differentially expressed genes (DEGs) in the
brain between PTSD and animal models of traumatic stress has been carried out. We
compared DEGs from the prefrontal cortex (PFC) of an established stress model to DEGs
from the dorsolateral PFC (dIPFC) of humans. We observed a significant enrichment
of rat DEGs in human PTSD and identified 20 overlapping DEGs, of which 17 (85%) are
directionally concordant. N,N-dimethyltryptamine (DMT) is a known indirect antioxidant,
anti-inflammatory, and neuroprotective compound with antidepressant and plasticity-facilitating
effects. We tested the capacity of DMT, the monoamine oxidase inhibitor (MAOI) harmaline,
and "pharmahuasca" (DMT + harmaline) to reduce reactive oxygen species (ROS) production
and inflammatory gene expression and to modulate neuroplasticity-related gene expression
in the model. We administered DMT (2 mg/kg IP), harmaline (1.5 mg/kg IP), pharmahuasca,
or vehicle every other day for 5 days, following a 30 day stress regiment. We measured
ROS production in the PFC and hippocampus (HC) by electron paramagnetic resonance
spectroscopy and sequenced total mRNA in the PFC. We also performed in vitro assays
to measure the affinity and efficacy of DMT and harmaline at SHT2AR compared to 5-HT.
DMT and pharmahuasca reduced ROS production in the PFC and HC, while harmaline had
mixed effects. Treatments normalized 9, 12, and 14 overlapping DEGs, and pathway analysis
implicated that genes were involved in ROS production, inflammation, growth factor
signaling, neurotransmission, and neuroplasticity.
